Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions

Hyvönen, M.T.; Smirnova, O.A.; Mitkevich, V.A.; Tunitskaya, V.L.; Karpov, D.S.; Khomutov, M.R.; Korolev, S.P.; Pietilä, M.; Ivanov, A.V.; Gottikh, M.B.; Vepsäläinen, J.; Alhonen, L.; Makarov, A.A.; Kochetkov, S.N.; Wallace, H.M.; Keinänen, T.A.; Khomutov, A.R.

Авторы: Hyvönen M.T., Smirnova O.A., Mitkevich V.A., Tunitskaya V.L., Karpov D.S., Khomutov M.R., Korolev S.P., Pietilä M., Ivanov A.V., Gottikh M.B., Vepsäläinen J., Alhonen L., Makarov A.A., Kochetkov S.N., Wallace H.M., Keinänen T.A., Khomutov A.R.
Журнал: International Journal of Molecular Sciences
Том: 23
Номер: 9
Год издания: 2022
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 1
Последняя страница: 17
Номер статьи: 4614
DOI: 10.3390/ijms23094614
Аннотация: The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the polyamine pool is the polyamine-inducible protein, antizyme 1 (OAZ1). OAZ1 inhibits polyamine uptake and targets ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, for proteasomal degradation. Here we report, for the first time, that polyamines induce dimerization of mouse recombinant full-length OAZ1, forming an (OAZ1)2–polyamine complex. Dimerization could be modulated by functionally active C-methylated spermidine mimetics (MeSpds) by changing the position of the methyl group along the Spd backbone—2-MeSpd was a poor inducer as opposed to 1-MeSpd, 3-MeSpd, and Spd, which were good inducers. Importantly, the ability of compounds to inhibit polyamine uptake correlated with the efficiency of the (OAZ1)2–polyamine complex formation. Thus, the (OAZ1)2–polyamine complex may be needed to inhibit polyamine uptake. The efficiency of polyamine-induced ribosomal +1 frameshifting of OAZ1 mRNA could also be differentially modulated by MeSpds—2-MeSpd was a poor inducer of OAZ1 biosynthesis and hence a poor downregulator of ODC activity unlike the other MeSpds. These findings offer new insight into the OAZ1-mediated regulation of polyamine homeostasis and provide the chemical tools to study it.
Добавил в систему: Королев Сергей Павлович

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